HP1 β and densely packed chromatin form separate microdomains in mouse ES cells, which are reconfigured upon exit from naïve pluripotency

Heterochromatin proteins play a key role in establishing local chromatin structure to control the transcription of target genes. Here we uncover a surprising segregation between regions of high DNA- and high heterochromatin protein 1 β (HP1 β )-density in mouse ES cells. DNA-low/HP1 β -high foci retain freely diffusing HP1 β , and form via condensation through a multitude of weak interactions on top of HP1 β that is bound stably to chromatin. DNA-high/HP1 β -low foci exclude freely diffusing HP1 β and display reduced chromatin mobility, suggesting a higher degree of chromatin self-interaction and a more repressive environment. Finally, the two types of environments are intertwined in DNA-high/HP1 β -high foci, where HP1 β maintains heterochromatin in a more compact yet dynamic chromatin state. During the exit from naïve pluripotency HP1 β is lost from regions of high DNA density as cells transition through the formative state, which might facilitate the reconfiguration of genome structure accompanying a change in cell state that we observed previously. Subsequently, as cells enter primed pluripotency, canonical heterochromatin is established.